Thalidomide

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Thalidomide
Thalidomide molecule
Systematic (IUPAC) name
(RS)-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione
Clinical data
Trade namesThalomid
AHFS/Drugs.commonograph
MedlinePlusa699032
Licence dataEMA:LinkUS FDA:link
Pregnancy cat.X (AU) X (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routesoral
Pharmacokinetic data
Protein binding55% and 66% for the (+)-R and (–)-S enantiomers, respectively
MetabolismHepatic (CYP2C19)[1]
Half-lifemean ranges from approximately 5 to 7 hours following a single dose; not altered with multiple doses
Identifiers
CAS number50-35-1 YesY
ATC codeL04AX02
PubChemCID 5426
DrugBankDB01041
ChemSpider5233 YesY
UNII4Z8R6ORS6L YesY
KEGGD00754 YesY
ChEBICHEBI:9513 N
ChEMBLCHEMBL468 YesY
Chemical data
FormulaC13H10N2O4 
Mol. mass258.23 g/mol–
 N (what is this?)  (verify)
 
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Thalidomide
Thalidomide molecule
Systematic (IUPAC) name
(RS)-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione
Clinical data
Trade namesThalomid
AHFS/Drugs.commonograph
MedlinePlusa699032
Licence dataEMA:LinkUS FDA:link
Pregnancy cat.X (AU) X (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routesoral
Pharmacokinetic data
Protein binding55% and 66% for the (+)-R and (–)-S enantiomers, respectively
MetabolismHepatic (CYP2C19)[1]
Half-lifemean ranges from approximately 5 to 7 hours following a single dose; not altered with multiple doses
Identifiers
CAS number50-35-1 YesY
ATC codeL04AX02
PubChemCID 5426
DrugBankDB01041
ChemSpider5233 YesY
UNII4Z8R6ORS6L YesY
KEGGD00754 YesY
ChEBICHEBI:9513 N
ChEMBLCHEMBL468 YesY
Chemical data
FormulaC13H10N2O4 
Mol. mass258.23 g/mol–
 N (what is this?)  (verify)

Thalidomide (/θəˈlɪdəmd/; from phthalimido-glutarimide[2]) was released into the market in 1957 in West Germany under the label of Contergan. The German drug company Grünenthal developed and sold the drug Thalidomide. Primarily prescribed as a sedative or hypnotic, thalidomide also claimed to cure “anxiety, insomnia, gastritis, and tension".[3] Afterwards it was used against nausea and to alleviate morning sickness in pregnant women. Thalidomide became an over the counter drug in Germany around 1960, and could be bought without a prescription. Shortly after the drug was sold, in Germany, between 5,000 and 7,000 infants were born with malformation of the limbs (phocomelia). Only 40% of these children survived.

The statistic was given that “50 percent of the mothers with deformed children had taken thalidomide during the first trimester of pregnancy.” Throughout Europe, Australia, and the United States, 10,000 cases were reported of infants with phocomelia; only 50% of the 10,000 survived. Those subjected to thalidomide while in the womb experienced limb deficiencies in a way that the long limbs either were not developed or presented themselves as stumps. Other effects included: deformed eyes, hearts, alimentary, and urinary tracts, and blindness and deafness.[4]

The negative effects of thalidomide led to the development of more structured drug regulations and control over drug use and development.[5] Pomalidomide, a derivative of thalidomide marketed by Celgene was approved in February 2013 by the U.S. Food and Drug Administration as a treatment for relapsed and refractory multiple myeloma.[6]

History[edit]

Development[edit]

Thalidomide was developed by German pharmaceutical company Grünenthal GmbH, who obtained a patent for it in 1954.[7] It was prescribed as a sedative, tranquilizer, and antiemetic for morning sickness.[8] Thalidomide, launched by Grünenthal on 1 October 1957,[9] was proclaimed a "wonder drug" for insomnia, coughs, colds and headaches. It was also found to be an effective antiemetic that had an inhibitory effect on morning sickness[citation needed]. During this time period the use of medications during pregnancy was not strictly controlled, and drugs were not thoroughly tested for potential harm to the fetus.[8] Thousands of pregnant women took the drug to relieve their symptoms. At the time of the drug's development, scientists did not believe any drug taken by a pregnant woman could pass across the placental barrier and harm the developing fetus,[5] even though the effect of alcohol on fetal development had been documented by case studies on alcoholic mothers since at least 1957.[10] There soon appeared reports of findings of abnormalities in children being born, traced back to the use of the drug thalidomide. In late 1959, it was noticed that peripheral neuritis developed in patients who took the drug over a period of time, and it was only after this point that thalidomide ceased to be provided over-the-counter.[11]

In Canada, the history of the drug thalidomide dates back to April 1, 1961. There were many different forms sold, with the most common variant being Talimol.[12] Two months after Talimol went on sale, pharmaceutical companies sent physicians letters warning about the risk of birth defects.[12] It was not until March 2, 1962 that both drugs were banned from the Canadian market by the FDD, and soon afterward physicians were warned to destroy their supplies.[12]

Birth defects crisis[edit]

Baby born to a mother who had taken thalidomide while pregnant.

In the late 1950s and early 1960s, more than 10,000 children in 46 countries were born with deformities such as phocomelia as a consequence of thalidomide use.[13] It is not known exactly how many worldwide victims of the drug there have been, although estimates range from 10,000 to 20,000.[14] Despite the side effects, thalidomide was sold in pharmacies in Canada until 1962; Canada was the last country to end sales of the drug.[12][15]

These artificial limbs were made for an affected child in the 1960s by the Department of Health and Social Security's Limb Fitting Centre in Roehampton, London

In the United Kingdom, the drug was licensed in 1958 and withdrawn in 1961. Of the approximately 2,000 babies born with defects, around half died within a few months and 466 survived to at least 2010.[16]

The Australian obstetrician William McBride and the German pediatrician Widukind Lenz suspected a link between birth defects and the drug, a theory Lenz proved in 1961.[17][18] McBride was later awarded a number of honors, including a medal and prize money by L'Institut de la Vie in Paris.[19]

The head of the East German central pharmacy control commission, Friedrich Jung, suspected an antivitaminic effect of thalidomide as derivative of glutamic acid.[20] It took some time before the increase in dysmelia at the end of the 1950s was connected with thalidomide. In 1958 Karl Beck, a former pediatric doctor in Bayreuth wrote an article in a local newspaper claiming a relationship between nuclear weapons testing and cases of dysmelia in children.[21] Based on this, FDP whip Erich Mende requested an official statement from the federal government.[21] For statistical reasons, the main data series used to research dysmelia cases started by chance at the same time as the approval date for thalidomide.[21] After the Nazi regime with its Law for the Prevention of Hereditarily Diseased Offspring used mandatory statistical monitoring to commit various crimes, western Germany had been very reluctant to monitor congenital disorders in a similarly strict way.[22] The parliamentary report rejected any relation with radioactivity and the abnormal increase of dysmelia.[21] Also the DFG research project installed after the Mende request was not helpful. The project was led by pathologist Franz Büchner who ran the project to propagate his teratological theory. Büchner saw lack of healthy nutrition and behavior of the mothers as being more important than genetic reasons.[22] Furthermore, it took a while to install a Surgeon General in Germany; the Federal Ministry of Health (Germany) was not founded until 1962, some months after thalidomide was banned from the market.[21] In Germany approximately 2,500 thalidomide babies were born.[18]

Several countries either restricted the drug's use or never approved it. Ingeborg Eichler, a member of the Austrian pharmaceutical admission conference enforced thalidomide (tradename Softenon) being sold under the rules of prescription medication and as a result relatively few affected children were born in Austria and Switzerland.[23] In the United States, pharmacologist Frances Oldham Kelsey M.D. withstood pressure from the Richardson-Merrell company and refused Food and Drug Administration (FDA) approval to market thalidomide, saying further studies were needed.[13] This reduced the impact of thalidomide in United States patients. Although thalidomide was never approved for sale in the United States at the time, millions of tablets had been distributed to physicians during a clinical testing program. It was impossible to know how many pregnant women had been given the drug to help alleviate morning sickness or as a sedative.[24]

Aftermath of scandal[edit]

1962: FDA pharmacologist Frances Oldham Kelsey receives the President's Award for Distinguished Federal Civilian Service from President John F. Kennedy for blocking sale of thalidomide in the United States.

For correctly denying the application despite the pressure from Richardson-Merrell, Kelsey eventually received the President's Award for Distinguished Federal Civilian Service at a 1962 ceremony with President John F. Kennedy. In September 2010, the FDA honored Kelsey with the first Kelsey award. The award, given annually to an FDA staff member, came 50 years after Kelsey, then a new medical officer at the agency, first reviewed the application from the William S. Merrell Company of Cincinnati.[25]

The numerous reports of malformations in babies brought about the awareness of the side effects of the drug on pregnant women. The birth defects caused by the drug thalidomide can range from moderate malformation to more severe forms. Possible birth defects include phocomelia, dysmelia, amelia, bone hypoplasticity, and other congenital defects affecting the ear, heart, or internal organs.[8] Franks et al. looked at how the drug affected newborn babies, the severity of their deformities, and reviewed the drug in its early years. Webb in 1963 also reviewed the history of the drug and the different forms of birth defects it had caused. “The most common form of birth defects from thalidomide is shortened limbs, with the arms being more frequently affected. This syndrome is the presence of deformities of the long bones of the limbs resulting in shortening and other abnormalities.”[12]

In 1968, after a long campaign by The Sunday Times, a compensation settlement for the UK victims was reached with Distillers Company (now part of Diageo), which had distributed the drug in the UK.[26][27] This compensation, which is distributed by the Thalidomide Trust in the UK, was substantially increased by Diageo in 2005.[28] The UK Government gave survivors a grant of £20 million, to be distributed through the Thalidomide Trust, in December 2009.[29]

Melbourne woman Lynette Rowe, who was born without limbs, is leading an Australian class action lawsuit against the drug's manufacturer, Grünenthal, which fought to have the case heard in Germany. The Victorian Supreme Court dismissed Grünenthal's application in 2012, and the case was heard in Australia. More than a hundred Australian thalidomide survivors are involved in the class action, according to Rowe's lawyer.[30] On 17 July 2012, Lynette Rowe was awarded an out-of-court settlement, believed to be in the millions of dollars and paving the way for class action victims to receive further compensation.

On 31 August 2012, Grünenthal chief executive Harold Stock apologized for the first time for producing the drug and remaining silent about the birth defects.[31] At a ceremony, Stock unveiled a statue of a disabled child to symbolize those harmed by thalidomide and apologized for not trying to reach out to victims for over 50 years. At the time of the apology, there were 5,000 to 6,000 sufferers still alive. Victim advocates called the apology "insulting" and "too little, too late", and criticized the company for not compensating victims. They also criticized the company for their claim that no one could have known the harm the drug caused, arguing that there were plenty of red flags at the time.[32]

The drug thalidomide's birth defects in children affected many people's lives, and from these events came the formation of the group called The Thalidomide Victims Association of Canada, a group of 120 Canadian survivors.[33] Their goal was to prevent future usage of drugs that could be of potential harm to mothers and babies. The members from the thalidomide victims association were involved in the STEPS program, which aimed to prevent teratogenicity.[8]

The effects of thalidomide increased fears regarding the safety of pharmaceutical drugs. The Society of Toxicology of Canada was formed after the events of thalidomide were made public, focusing on toxicology as a discipline separate from pharmacology.[34] The need for the testing and approval of the toxins in certain pharmaceutical drugs became more important after the disaster. The Society of Toxicology of Canada is responsible for the Conservation Environment Protection Act, focusing on researching the impact to human health of chemical substances.[34] Thalidomide brought on changes in the way drugs are tested, what type of drugs are used during pregnancy, and increased the awareness of potential side effects of drugs.

Change in drug regulations[edit]

The disaster prompted many countries to introduce tougher rules for the testing and licensing of drugs, such as the Kefauver-Harris Amendment[35] (U.S.) and Directive 65/65/EEC1 (E.U.).[36]

In his book Pharmageddon, David Healy says that the United States Congress wanted to prevent a recurrence of the thalidomide tragedy, and sought to limit the marketing excesses of the pharmaceutical industry. So new drug development was rewarded with product rather than process patents, and new drugs were made available only through prescription. Also, new medications had to prove that they worked in controlled trials before they reached the market. On the 50th anniversary of the 1962 FDA bill enacted by Congress, Pharmageddon shows how these arrangements have not been successful and have actually led to an escalating number of drug induced deaths and injuries.[37]

Possible indications[edit]

After being removed from the pharmaceutical market, thalidomide has been the subject of significant clinical research. To prevent birth defects, Celgene developed the STEPS protocol for clinical trials, which monitors trial participants for signs of pregnancy and requires use of two forms of contraception to prevent birth defects.[38] The drug has since shown promise in the treatment of leprosy and certain forms of cancer.

Research also suggests that thalidomide is useful in treating complications of infection with HIV, such as wasting syndrome, nausea, and prurigo nodularis.[39] However, it was also found that thalidomide's toxic side-effects are less well-tolerated in HIV patients, requiring caution during treatment.

Thalidomide has also been found to be effective in treating actinic prurigo, an autoimmune skin disease.[40] Thalidomide has been used in chronic bullous dermatosis of childhood (CBDC) with encouraging results.[41] Peripheral neuritis may be a limiting factor for long term use of thalidomide.

Studies carried out in animal models have suggested the use of combined therapy with thalidomide and glucantime could have a therapeutic benefit in the treatment of visceral leshmaniasis.[42]

A study published in April 2010 discussed the ability of thalidomide to induce vessel maturation, which may be useful as a therapeutic strategy for the treatment of vascular malformations. The research was conducted in an experimental model of the genetic disease hereditary hemorrhagic telangiectasia.[43]

Leprosy treatment[edit]

In 1964, biologist Jacob Sheskin administered thalidomide to a patient critically ill with leprosy. The patient exhibited erythema nodosum leprosum (ENL), a painful skin condition, one of the complications of leprosy. This was attempted despite the ban on thalidomide's use, but results were favorable: the patient slept for hours and was able to get out of bed without aid upon awakening. A clinical trial studying the use of thalidomide in leprosy soon followed.[44]

Thalidomide has been used by Brazilian physicians as the drug of choice for the treatment of severe ENL since 1965, and by 1996, at least 33 cases of thalidomide embryopathy were recorded in people born in Brazil after 1965.[45] Since 1994, the production, dispensing, and prescription of thalidomide have been strictly controlled, requiring women to use two forms of birth control and submit to regular pregnancy tests. Despite this, cases of thalidomide embryopathy continue,[46][47] with at least 100 cases identified in Brazil between 2005 and 2010.[48] 5.8 million thalidomide pills were distributed throughout Brazil in this time period, largely to poor Brazilians in areas with poor access to healthcare, and these cases have occurred despite the controls.

In 1990 a group of researchers in Brazil noted that TNF alpha levels went up in leprosy reactional states[49] and observed that TNF levels decreased in some patients on treatment with thalidomide. A research fellow was sent to explore the mechanism of this effect to the lab of Gina Kaplan at Rockefeller university. Further work conducted in 1991 by Kaplan and the Brazilian fellow at Rockefeller University in New York City showed that thalidomide decreased TNF alpha levels in leprosy by enhancing the degradation of its mRNA. Kaplan believed thalidomide could be an effective treatment for AIDS given the cachectic effects of TNF alpha in this disease. She partnered with Celgene to further develop the potential for thalidomide in AIDS and tuberculosis.

In 1998 the FDA approved the drug's use in the treatment of ENL.[50] Because of thalidomide's potential for causing birth defects, the drug may be distributed only under tightly controlled conditions. The FDA required that Celgene Corporation, which planned to market thalidomide under the brand name Thalomid, establish a system for thalidomide education and prescribing safety (STEPS) oversight program. The conditions required under the program include limiting prescription and dispensing rights only to authorized prescribers and pharmacies, keeping a registry of all patients prescribed thalidomide, providing extensive patient education about the risks associated with the drug, and providing periodic pregnancy tests for women who take the drug.[50]

More recently, the World Health Organisation (WHO) has stated:

"The WHO does not recommend the use of thalidomide in leprosy as experience has shown that it is virtually impossible to develop and implement a fool-proof surveillance mechanism to combat misuse of the drug. The drug clofazimine is now a component of the multidrug therapy (MDT), introduced by WHO in 1981 as the standard treatment for leprosy and now supplied free of charge to all patients worldwide."[51]

Cancer treatment[edit]

In the 2000s, the combination of thalidomide and dexamethasone, often in combination with melphalan, became one of the most common regimens for patients with newly diagnosed multiple myeloma.[52][53] Thalidomide may also cause side effects, such as polyneuropathy, fatigue, skin rash, and venous thromboembolism (VTE), or blood clots, which could lead to stroke or myocardial infarction.[54][55] Because of the high incidence of VTEs—as high as 26%—a black box warning was added in the United States in 2006 to the package insert for thalidomide, indicating that patients with multiple myeloma who receive thalidomide-dexamethasone may benefit from concurrent thromboembolism prophylaxis or aspirin.

In 2006 the U.S. Food and Drug Administration granted accelerated approval for thalidomide in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma patients.[56] The FDA approval came seven years after the first reports of efficacy in the medical literature[57] and Celgene took advantage of "off-label" marketing opportunities to promote the drug in advance of its FDA approval for the myeloma indication. Over $300 million worth of Thalomid, as the drug is commercially known, was sold in 2004, while approved only for leprosy.[58]

All physicians prescribing and patients receiving thalidomide must go through the STEPS process to ensure that no more children are born with birth defects traceable to the medication. Celgene has sponsored numerous clinical trials with analogues to thalidomide, such as lenalidomide, that are substantially more powerful and have fewer side effects — except for greater myelosuppression.[59]

In 2012, Health Canada recognized that Thalomid used in multiple myeloma treatment may increase the risk of other cancers, and updated the medication label to include this new safety information.[60]

Interest turned to Pomalidomide, a derivative of thalidomide marketed by Celgene. It is a very active anti-angiogenic and also acts as an immunomodulator. Pomalidomide was approved in February 2013 by the U.S. Food and Drug Administration (FDA) as a treatment for relapsed and refractory multiple myeloma.[6] It received a similar approval from the European Commission in August 2013, and is expected to be marketed in Europe under the brand name Imnovid.[61]

Teratogenic mechanism[edit]

The mechanism of thalidomide's teratogenic action has led to over 2000 research papers and the proposal of 15 or 16 plausible mechanisms.[62] Angiogenesis is critical during limb development of the fetus. Thalidomide can directly inhibit angiogenesis induced by bFGF or VEGF in vivo.[63] Teratogenic analogs inhibit angiogenesis whereas nonteratogenic analogs do not inhibit angiogenesis.[63] In 2009, research by other groups confirmed "conclusively that loss of newly formed blood vessels is the primary cause of thalidomide teratogenesis, and developing limbs are particularly susceptible because of their relatively immature, highly angiogenic vessel network".[64] Thus the accepted theory is that inhibition of angiogenesis is the mechanism of teratogenicity as originally proposed by D'Amato in 1994.

The two enantiomers of thalidomide:
Left: (S)-thalidomide
Right: (R)-thalidomide

Thalidomide is racemic; the individual enantiomers can racemize due to the acidic hydrogen at the chiral center, and this process can occur in vivo[65][66][67][68] so any plan to administer a purified single enantiomer to avoid the teratogenic effects will most likely be in vain.[69][70][67]

Inactivation of the protein cereblon[edit]

Thalidomide binds to and inactivates the protein cereblon, which is important in limb formation[14] and leads to a teratogenic effect on fetal development. This was confirmed in studies that reduced the production of cereblon in developing chick and zebrafish embryos using genetic techniques. These embryos had defects similar to those treated with thalidomide. While the mechanism that causes teratogenicity has been established, the mechanism for therapeutic effects remains unclear.[71]

Thalidomide analogs[edit]

The exploration of the antiangiogenic and immunomodulatory activities of thalidomide has led to the study and creation of thalidomide analogs.[72] In 2005 Celgene received FDA approval for lenalidomide (Revlimid) as the first commercially useful derivative. Revlimid is available only in a restricted distribution setting to avoid its use during pregnancy. Further studies are being conducted to find safer compounds with useful qualities. Another more potent analog, pomalidomide, is now FDA approved.[73] These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight two conditions.[74]

Notable people affected[edit]

See also[edit]

References[edit]

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